The regulation of the cell cycle is mainly influenced by a series of serine/threonine kinases. Such serine/threonine kinases are also called cyclin-dependent kinases (CDKs), and they promote the progression of the cell cycle, the transcription of the genetic information and the normal division and proliferation of cells by binding to their corresponding cyclins which are regulatory subunits. CDK4/6 is a key regulator of the cell cycle and is capable of triggering the transition of the cell cycle from the growth phase (G1 phase) to the DNA replication phase (51 phase). During the cell proliferation, a complex formed by Cyclin D and CDK4/6 is capable of phosphorylating the retinoblastoma protein (Rb). Once the tumor suppressor protein Rb is phosphorylated, its transcription factor E2F which binds tightly to the tumor suppressor protein Rb in an unphosphorylated state may be released. The activation of E2F further transcribes, which promotes the cell cycle to pass the restriction point (R point) and proceed from the G1 phase to the S phase, leading to the cycle of cell proliferation. Therefore, inhibiting CDK4/6 from forming the Cyclin D-CDK4/6 complex is capable of blocking the progression of the cell cycle from the G1 phase to the S phase, thereby achieving the purpose of inhibiting the tumor proliferation. In estrogen receptor positive (ER+) breast cancer (BC), CDK4/6 is frequently overactive while CDK4/6 is a key downstream target of ER signaling. Preclinical data indicates that the dual inhibition of CDK4/6 and estrogen receptor (ER) signaling has a synergistic effect and is capable of inhibiting the growth of estrogen receptor positive (ER+) breast cancer (BC) cells in the G1 phase.
CDK4/6 as a target is a highly competitive field of research and development. Pietzsch summarized the progress in this field in 2010 (Mini-Rev. Med. Chem. 2010, 10, 527-539). Malorni also summarized the research results of the latest CDK4/6 inhibitors in the preclinical and clinical studies of breast cancer in 2014 (Curr. Opin. Oncol. 2014, 26, 568-575). Extensive research efforts on CDK4/6 target contribute to the development of a series of different selective CDK inhibitors, and also lead to the discovery of a few effective and highly selective CDK4/6 inhibitors. Palbociclib (PD0332991) is one of these effective and highly selective CDK4/6 inhibitors. It has entered human clinical trials and is used for the treatment of women with advanced or metastatic estrogen receptor positive (ER+) and human epidermal growth factor receptor 2 negative (HER2-) breast cancer. Based on the mid-term data of the PALOMA-1 trial, Pfizer submitted a new drug application (NDA) for palbociclib to the FDA in August 2014. The FDA approved the request of launching palbociclib in February 2015. Two other CDK4/6 inhibitors, Abemaciclib (LY2835219) and LEE-011, have also begun to recruit patients with cancer for the Phase 3 clinical trials. In addition to being useful in the treatment of breast cancer, these small-molecule heterocyclic compounds are clinically useful in the treatment of a variety of other cancers. These patents include WO2012018540, WO2012129344, WO2011101409, WO2011130232, WO2010075074, WO2009126584, WO2008032157, and WO2003062236.
